ALPHA SYNUCLEIN IN MODELS OF MSA

多系统萎缩(MSA)的主要病理特征是少突胶质细胞中的胶质细胞质包涵体(GCI)。GCI的一个主要成分是α-突触核蛋白。在一系列研究中，我们将在过量表达α-突触核蛋白的转基因(TG)小鼠系中进行，我们将检查似乎有助于α-突触核蛋白积累和聚集的因素。具体目的1.我们假设，在某些神经启动子控制下过表达h[α]-突触核蛋白的转基因小鼠会在少突胶质细胞和/或神经元中积聚h[α]-突触核蛋白，并可能导致GCI样改变的形成。我们建立了一个TG小鼠品系，其中h[α]-突触核蛋白是 在血小板衍生生长因子B(PDGF-B)启动子的控制下过度表达，这些转基因小鼠表现出运动障碍和h[α]-突触核蛋白在少突胶质细胞和神经元中的积聚。我们通过将h[α]-突触核蛋白转基因置于髓鞘碱性蛋白(MBP)启动子的控制下，建立了一个tg小鼠品系，在该品系中，α-突触核蛋白的靶向仅在少突胶质细胞中过表达。两个品系的转基因小鼠都将接受详细的行为、神经化学和神经病理分析。具体目标2.我们假设氧化应激有利于h[α]-突触核蛋白的积累。为了研究这些因素的影响，将两个品系的Tg h[α]-突触核蛋白小鼠分别与超氧化物歧化酶1、超氧化物歧化酶2和谷胱甘肽过氧化物酶基因敲除小鼠杂交。动物将接受特定目标1、特定目标3的分析。我们假设硝化作用有利于h[α]-突触核蛋白的积累。为了研究这些因素的影响，将两种品系的TG h[α]-突触核小鼠分别与神经元型一氧化氮合酶(NNOS)和诱导型一氧化氮合酶(INOS)基因敲除小鼠杂交。这些动物将接受具体目标1中的分析。

The cardinal pathological feature of multiple system atrophy (MSA) is the glial cytoplasmic inclusion (GCI), which is found in oligodendrocytes. A major component of the GCI is alpha-synuclein. In a series of studies, which will be carried out in transgenic (tg) mouse lines overexpressing alpha-synuclein, we will examine factors that appear to contribute to the accumulation and aggregation of alpha-synuclein. Specific Aim 1. We hypothesize those tg mice overexpressing h[alpha]-synuclein under the control of certain neural promoters will accumulate h[alpha]-synuclein in oligodendrocytes and/or neurons and may result in formation of GCI-like alterations. We have established a tg mouse line, in which h[alpha]-synuclein is overexpressed under the control of the platelet-derived growth factor B (PDGF-B) promoter, and these tg mice demonstrate motoric deficits and accumulation of h[alpha]-synuclein in oligodendrocytes and neurons. We have established a tg mouse line in which alpha-synuclein is targeted to be overexpressed in only oligodendrocytes by placing the h[alpha]-synuclein transgene under the control of the myelin basic protein (MBP) promoter. Both strains of tg mice will undergo detailed behavioral, neurochemical and neuropathological analyses. Specific Aim 2. We hypothesize that oxidative stress favors the accumulation of h[alpha]-synuclein. To study the effects of these factors, both strains of tg h[alpha]-synuclein mice will be crossed with superoxide dismutase (SOD) 1, SOD 2 and glutathione peroxidase knockout mice. The animals will undergo analyses as in Specific Aim 1. Specific Aim 3. We hypothesize that nitration favors the accumulation of h[alpha]-synuclein. To study the effects of these factors, both strains of tg h[alpha]-synuclein mice will be crossed with neuronal nitric oxide synthase (nNOS) and inducible NOS (iNOS) knockout mice. The animals will undergo analyses as in Specific Aim 1.